Synaptic plasticity is the main mechanism allowing storage of memories and underlies adaptive changes in behavior. As in the hippocampus, both LTP and LTD of the Medium Spiny Neurons (MSN), the projection neurons of the striatum, require elevation of intracellular calcium, but the role of calcium is more elusive in the MSN mostly due to the critical role of dopamine in plasticity. Understanding how the interactions between calcium dynamics and dopamine (via PKA) control synaptic plasticity requires a novel, data-driven modeling approach to study calcium dynamics. A tightly knit collaboration between electrophysiology, calcium imaging, calcium dynamics modeling can for the first time provide a unified understanding of mechanism underlying plasticity. The overall goal of this project is to predict the development of synaptic plasticity direction and magnitude from the stimulation parameters that control neuronal calcium dynamics. This goal is achieved through the following aims: Aim 1: Test the hypothesis that dopamine, via PKA, increases the difference between NMDA receptor mediated and VDCC mediated calcium influx. Aim 2: Investigate how the PKA mediated change in calcium influx through NMDA receptor and CaL channels alters synaptic plasticity. Aim 3: Demonstrate that synaptic plasticity rules can explain in vivo synaptic plasticiy, and the change in plasticity caused by the dopamine depletion of Parkinson's Disease. The aims are achieved through cycles of model development and prediction followed by electrophysiology and calcium imaging experiments. The proposed research, as well as future investigations of the calcium dynamics in other cell types, is enabled by development and integration of software for parameter optimization with multi-compartmental, multi-ion channel neuron models of realistic calcium dynamics. Demonstrating a relationship between calcium dynamics and striatal synaptic plasticity has implications far beyond striatal plasticity. Modeling the complexity of calcium handling in neurons will expand the range of cell types and stimulation protocols that can be correlated with synaptic plasticity outcomes. The key role of dopamine in several devastating neuronal disorders places dopamine as a central issue from the perspective of health policies, and it is likely that the study of the dopaminergic control of plasticity inducion will contribute to the understanding of several pathologies and to the identification of original therapeutic targets. Changes in synaptic plasticity due to Parkinson's and addiction are partly due to the dopamine mediated changes in NMDA receptor composition and calcium influx. Exposure to and withdrawal from drugs of abuse cause alteration in NMDA receptors and synaptic plasticity. Thus understanding the interaction between calcium and dopamine in striatal synaptic plasticity will illuminate mechanisms underlying normal memory storage, and also the abnormal plasticity observed in Parkinson's disease, and chronic drug and alcohol abuse. Moreover, dopamine exerts a major influence on the general motivational organization of behavior. Uncovering the action of dopamine thus reaches further than the understanding of aspects of brain functions, as it may touch on the organization of individuals within social structures. The broader impacts include development of software tools and cross-disciplinary education and training. The multi-scale modeling software tools will be made available (in open source form) to the community. This software is broadly applicable not only to address major questions in neuroscience, but also to other physiological systems, such as cardiology where signaling pathways interact with electrical properties. More importantly, the modeling software employs a declarative language with parameter names taken from biochemistry, such that the software is intuitive for experimentalists to learn. This project will provide a uniquely cross-disciplinary environment for training students and post-doctoral fellows. The trainees from this program will be uniquely positioned to develop the field of data driven modeling of signaling pathways. The PIs have extensive track records of international cross-disciplinary instruction, with tutorial material on modeling signaling pathways made publicly available.